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1.  Association of genetic variation in FTO with risk of obesity and type 2 diabetes with data from 96,551 East and South Asians 
Diabetologia  2011;55(4):981-995.
FTO harbours the strongest known obesity-susceptibility locus in Europeans. While there is growing evidence for a role for FTO in obesity risk in Asians, its association with type 2 diabetes, independently of BMI, remains inconsistent. To test whether there is an association of the FTO locus with obesity and type 2 diabetes, we conducted a meta-analysis of 32 populations including 96,551 East and South Asians.
All studies published on the association between FTO-rs9939609 (or proxy [r2 > 0.98]) and BMI, obesity or type 2 diabetes in East or South Asians were invited. Each study group analysed their data according to a standardised analysis plan. Association with type 2 diabetes was also adjusted for BMI. Random-effects meta-analyses were performed to pool all effect sizes.
The FTO-rs9939609 minor allele increased risk of obesity by 1.25-fold/allele (p = 9.0 × 10−19), overweight by 1.13-fold/allele (p = 1.0 × 10−11) and type 2 diabetes by 1.15-fold/allele (p = 5.5 × 10−8). The association with type 2 diabetes was attenuated after adjustment for BMI (OR 1.10-fold/allele, p = 6.6 × 10−5). The FTO-rs9939609 minor allele increased BMI by 0.26 kg/m2 per allele (p = 2.8 × 10−17), WHR by 0.003/allele (p = 1.2 × 10−6), and body fat percentage by 0.31%/allele (p = 0.0005). Associations were similar using dominant models. While the minor allele is less common in East Asians (12–20%) than South Asians (30–33%), the effect of FTO variation on obesity-related traits and type 2 diabetes was similar in the two populations.
FTO is associated with increased risk of obesity and type 2 diabetes, with effect sizes similar in East and South Asians and similar to those observed in Europeans. Furthermore, FTO is also associated with type 2 diabetes independently of BMI.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2370-7) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3296006  PMID: 22109280
Asians; FTO; Meta-analysis; Obesity; Type 2 diabetes
2.  Corneal changes after a single session of selective laser trabeculoplasty for open-angle glaucoma 
Eye  2013;28(1):47-52.
To investigate the changes in endothelial cell count, central corneal thickness (CCT), and refractive error after a session of selective laser trabeculoplasty (SLT) for open angle glaucoma (OAG).
This prospective cohort study recruited 111 eyes of 66 consecutive subjects with OAG. Subjects received SLT to 360° of the trabecular meshwork. Endothelial cell count, CCT, and spherical equivalent were measured at baseline before SLT as well as at 1 week and 1 month post SLT. A repeated measure nested ANOVA with Tukey's multiple comparison test was performed to compare the outcome measures before and after SLT.
In 111 eyes of 66 subjects, the mean number of laser applications per treatment was 166.9±41.4 with a mean energy level of 1.0±0.07 mJ. The mean endothelial cell count decreased significantly from 2465.0±334.0 cells/mm2 at baseline to 2355.0±387.0 cells/mm2 at 1 week (P=0.0004) but increased to baseline levels at 1 month post SLT (2424.0±379.4 cells/mm2, P=0.3). The CCT, which decreased from a baseline of 549.4±37.6 to 543.9±40.2 μm at 1 week post SLT (P=0.02), also returned to the baseline level by 1 month (P=0.2). The spherical equivalent was static from baseline. A positive correlation was found between total laser energy and CCT at 1 month post treatment (r=0.3, P=0.005).
The transient reductions in endothelial cell count and CCT following SLT returned to baseline levels 1 month after the procedure. Patients undergoing SLT should be aware of the risk of potential corneal changes.
PMCID: PMC3890760  PMID: 24136571
selective laser trabeculplasty; endothelial cell count; central cornea thickness; spherical equivalent; cornea
3.  Maternal history of diabetes is associated with increased cardiometabolic risk in Chinese 
Nutrition & Diabetes  2014;4(3):e112-.
Positive family history is associated with increased type 2 diabetes (T2D) risk, and reflects both genetic and environmental risks. Several studies have suggested an excess maternal transmission of T2D, although the underlying mechanism is unknown. We aimed to examine the association between maternal diabetes and cardiometabolic risk in the offspring.
Parental history of diabetes and clinical data including anthropometric traits, fasting plasma glucose and insulin (FPG, FPI), blood pressure and lipid profile were collected from 2581 unrelated Chinese offspring (2026 adolescents from a population-based school survey and 555 adults from a community-based health screening programme). A subset of subjects (n=834) underwent oral glucose tolerance test to measure the glucose and insulin concentrations at 0, 15, 30, 60 and 120 min for evaluation of the areas under the curve (AUC) of glucose and insulin at 0–120 min, homoeostasis model assessment of insulin resistance (HOMA-IR) and bell-cell function, insulinogenic index, insulin sensitivity index (ISI) and oral disposition index (DI).
A positive parental history of diabetes was associated with increased risk of obesity (odd ratios (OR) (95% confidence interval (CI))=1.48 (1.10–2.00)), central obesity (OR (95% CI)=1.67 (1.21–2.32)), higher FPI, HOMA-IR, 2-h insulin, AUC of glucose at 0–120 min, triglycerides, reduced ISI and DI. Compared with individuals without parental diabetes, offspring with diabetic mother had significantly increased risk of obesity (OR (95% CI)=1.59 (1.07–2.35)), central obesity (OR (95% CI)=1.88 (1.23–2.88)), higher glucose levels and BP, were more insulin resistant but also had impaired first-phase insulin response and worse lipid profile. However, paternal history of diabetes had no effect on any of the studied traits, except higher body mass index, waist circumference in females and FPG.
Our findings suggested that maternal history of diabetes conferred increased risk of cardiometabolic abnormalities, and was associated with both insulin resistance and impaired first-phase insulin secretion. Further investigation into the mechanism of transgenerational diabetes is warranted.
PMCID: PMC3974036  PMID: 24614663
4.  Genome-wide association study in a Chinese population identifies a susceptibility locus for type 2 diabetes at 7q32 near PAX4 
Diabetologia  2013;56(6):1291-1305.
Most genetic variants identified for type 2 diabetes have been discovered in European populations. We performed genome-wide association studies (GWAS) in a Chinese population with the aim of identifying novel variants for type 2 diabetes in Asians.
We performed a meta-analysis of three GWAS comprising 684 patients with type 2 diabetes and 955 controls of Southern Han Chinese descent. We followed up the top signals in two independent Southern Han Chinese cohorts (totalling 10,383 cases and 6,974 controls), and performed in silico replication in multiple populations.
We identified CDKN2A/B and four novel type 2 diabetes association signals with p < 1 × 10−5 from the meta-analysis. Thirteen variants within these four loci were followed up in two independent Chinese cohorts, and rs10229583 at 7q32 was found to be associated with type 2 diabetes in a combined analysis of 11,067 cases and 7,929 controls (pmeta = 2.6 × 10−8; OR [95% CI] 1.18 [1.11, 1.25]). In silico replication revealed consistent associations across multiethnic groups, including five East Asian populations (pmeta = 2.3 × 10−10) and a population of European descent (p = 8.6 × 10−3). The rs10229583 risk variant was associated with elevated fasting plasma glucose, impaired beta cell function in controls, and an earlier age at diagnosis for the cases. The novel variant lies within an islet-selective cluster of open regulatory elements. There was significant heterogeneity of effect between Han Chinese and individuals of European descent, Malaysians and Indians.
Our study identifies rs10229583 near PAX4 as a novel locus for type 2 diabetes in Chinese and other populations and provides new insights into the pathogenesis of type 2 diabetes.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-013-2874-4) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3648687  PMID: 23532257
Chinese; Diabetes; East Asians; Genetics; Genome-wide association study
5.  Pharmacological reduction of NEFA restores the efficacy of incretin-based therapies through GLP-1 receptor signalling in the beta cell in mouse models of diabetes 
Diabetologia  2012;56(2):423-433.
Type 2 diabetes mellitus is associated with reduced incretin effects. Although previous studies have shown that hyperglycaemia contributes to impaired incretin responses in beta cells, it is largely unknown how hyperlipidaemia, another feature of type 2 diabetes, contributes to impaired glucagon-like peptide 1 (GLP-1) response. Here, we investigated the effects of NEFA on incretin receptor signalling and examined the glucose-lowering efficacy of incretin-based drugs in combination with the lipid-lowering agent bezafibrate.
We used db/db mice to examine the in vivo efficacy of the treatment. Beta cell lines and mouse islets were used to examine GLP-1 and glucose-dependent insulinotropic peptide receptor signalling.
Palmitate treatment decreased Glp1r expression in rodent insulinoma cell lines and isolated islets. This was associated with impairment of the following: GLP-1-stimulated cAMP production, phosphorylation of cAMP-responsive elements binding protein (CREB) and insulin secretion. In insulinoma cell lines, the expression of exogenous Glp1r restored cAMP production and the phosphorylation of CREB. Treatment with bezafibrate in combination with des-fluoro-sitagliptin or exendin-4 led to more robust glycaemic control, associated with improved islet morphology and beta cell mass in db/db mice.
Elevated NEFA contributes to impaired responsiveness to GLP-1, partially through downregulation of GLP-1 receptor signalling. Improvements in lipid control in mouse models of obesity and diabetes increase the efficacy of incretin-based therapy.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-012-2776-x) contains peer-reviewed but unedited supplementary material, which is available to authorised users.
PMCID: PMC3536946  PMID: 23188390
Dipeptidyl peptidase-4; Exendin-4; Glucagon-like peptide 1; Glucose-dependent insulinotropic polypeptide; Islet; NEFA; Non-esterified fatty acid; Receptor
6.  Effects of olmesartan on renal and cardiovascular outcomes in type 2 diabetes with overt nephropathy: a multicentre, randomised, placebo-controlled study 
Diabetologia  2011;54(12):2978-2986.
The renal and cardiovascular protective effects of angiotensin receptor blocker (ARB) remain controversial in type 2 diabetic patients treated with a contemporary regimen including an angiotensin converting enzyme inhibitor (ACEI).
We examined the effects of olmesartan, an ARB, on primary composite outcome of doubling of serum creatinine, endstage renal disease and death in type 2 diabetic patients with overt nephropathy. Secondary outcome included composite cardiovascular outcomes, changes in renal function and proteinuria. Randomisation and allocation to trial group were carried out by a central computer system. Participants, caregivers, the people carrying out examinations and people assessing the outcomes were blinded to group assignment.
Five hundred and seventy-seven (377 Japanese, 200 Chinese) patients treated with antihypertensive therapy (73.5% [n = 424] received concomitant ACEI), were given either once-daily olmesartan (10–40 mg) (n = 288) or placebo (n = 289) over 3.2 ± 0.6 years (mean±SD). In the olmesartan group, 116 developed the primary outcome (41.1%) compared with 129 (45.4%) in the placebo group (HR 0.97, 95% CI 0.75, 1.24; p = 0.791). Olmesartan significantly decreased blood pressure, proteinuria and rate of change of reciprocal serum creatinine. Cardiovascular death was higher in the olmesartan group than the placebo group (ten vs three cases), whereas major adverse cardiovascular events (cardiovascular death plus non-fatal stroke and myocardial infarction) and all-cause death were similar between the two groups (major adverse cardiovascular events 18 vs 21 cases, all-cause deaths; 19 vs 20 cases). Hyperkalaemia was more frequent in the olmesartan group than the placebo group (9.2% vs 5.3%).
Olmesartan was well tolerated but did not improve renal outcome on top of ACEI.
Trial registration: NCT00141453
Funding: The ORIENT study was supported by a research grant from Daiichi Sankyo.
Electronic supplementary material
The online version of this article (doi:10.1007/s00125-011-2325-z) contains peer-reviewed but unedited supplementary material, including a list of the ORIENT study investigators, which is available to authorised users.
PMCID: PMC3210358  PMID: 21993710
Angiotensin receptor blocker; Diabetic nephropathy; Macroproteinuria; Type 2 diabetes
7.  Comparison of enalapril and nifedipine in treating non-insulin dependent diabetes associated with hypertension: one year analysis. 
BMJ : British Medical Journal  1992;305(6860):981-985.
OBJECTIVES--To compare the efficacy, safety, and tolerance of enalapril and nifedipine in hypertensive patients with non-insulin dependent diabetes. DESIGN--One year double blind follow up of patients randomly allocated to either enalapril or nifedipine with matching placebos for the alternative drug. SETTING--Metabolic Investigation Unit, Hong Kong. SUBJECTS--102 patients were randomised: 52 to nifedipine and 50 to enalapril. At baseline 44 patients had normoalbuminuria, 36 microalbuminuria, and 22 macroalbuminuria. MAIN OUTCOME MEASURES--Blood pressure, albuminuria, and parameters of renal function and glycaemic control. RESULTS--In patients who completed one year's treatment the median dose required by the nifedipine group (n = 49) was 60 mg/day; seven (14%) required additional diuretics. Of 41 patients given enalapril, 37 required the maximum dose (40 mg/day) and 27 (76%) required diuretics. At one year mean arterial blood pressures were similar in both groups. Albuminuria fell by 54% in the enalapril group and 11% in the nifedipine group (p = 0.006). Fractional albumin clearance ratio fell by 47% in the enalapril group and increased by 3% in the nifedipine group (p = 0.009). Creatinine clearance fell similarly in both groups but plasma creatinine concentration was increased by 20% in the enalapril group versus 8% in the nifedipine group (p = 0.001). CONCLUSION--Patients taking enalapril often required diuretics to control blood pressure. Enalapril reduced proteinuria significantly more than nifedipine in the microalbuminuric and macroalbuminuric patients but increased plasma creatinine concentrations. Longer follow up is required to clarify the importance of enalapril's antiproteinuric effect.
PMCID: PMC1883996  PMID: 1458144
9.  Inactivation of the gene for anticoagulant protein C causes lethal perinatal consumptive coagulopathy in mice. 
Journal of Clinical Investigation  1998;102(8):1481-1488.
Matings of mice heterozygous for a protein C (PC) deficient allele, produced by targeted PC gene inactivation, yielded the expected Mendelian distribution of PC genotypes. Pups with a total deficiency of PC (PC-/-), obtained at embryonic day (E) 17.5 and at birth, appeared to develop normally macroscopically, but possessed obvious signs of bleeding and thrombosis and did not survive beyond 24 h after delivery. Microscopic examination of tissues and blood vessels of E17.5 PC-/- mice revealed their normal development, but scattered microvascular thrombosis in the brain combined with focal necrosis in the liver was observed. In addition, bleeding was noted in the brain near sites of fibrin deposition. The severity of these pathologies was exaggerated in PC-/- neonates. Plasma clottable fibrinogen was not detectable in coagulation assays in PC-/- neonatal mice, suggestive of fibrinogen depletion and secondary consumptive coagulopathy. Thus, while total PC deficiency did not affect the anatomic development of the embryo, severe perinatal consumptive coagulopathy occurred in the brain and liver of PC-/- mice, suggesting that a total PC deficiency is inconsistent with short-term survival.
PMCID: PMC508997  PMID: 9788960
11.  Obesity, albuminuria and hypertension among Hong Kong Chinese with non-insulin-dependent diabetes mellitus (NIDDM). 
Postgraduate Medical Journal  1993;69(809):204-210.
A total of 412 Hong Kong Chinese diabetic patients were studied on at least two occasions 8-16 weeks apart. Although 28% were insulin-treated, only 3.6% had insulin-dependent diabetes (IDDM). In the remaining 397 patients with non-insulin-dependent diabetes (NIDDM), the mean (s.d.) body mass index (BMI) was 24.4 +/- 3.2 kg/m2 in females and 24.2 +/- 3.2 kg/m2 in males. Obesity was present in 17% of males (BMI > 27 kg/m2) and 40% of females (BMI > 25 kg/m2). Established hypertension was present in 49%. Abnormal albuminuria, defined as a mean urinary albumin/creatinine (UA/Cr) ratio greater than 5.4 mg/mmol based on two random spot urine samples, was present in 47%. On stepwise multiple regression analysis, UA/Cr ratio (R2 = 0.34, F = 65.4, P < 0.001) showed significant associations with systolic blood pressure (standardized regression coefficient beta = 0.40, P < 0.001), plasma creatinine concentration (beta = 0.27, P < 0.001) and glycosylated haemoglobin (beta = 0.20, P < 0.001). While the prevalence of hypertension increased with increasing severity of proteinuria, 40% of normoalbuminuric patients had hypertension. Among patients diagnosed before the age of 35 (n = 67), 52% were insulin-treated although only 10% were insulin-dependent. Among these NIDDM patients of young onset (n = 59), obesity was present in 25% of males and 56% of females. Overall, 18% of these patients had a blood pressure greater than 140/90 mmHg and 27% had abnormal albuminuria. In Hong Kong Chinese, diabetes mellitus is predominantly non-insulin-dependent even in the young. Obesity is more prevalent among females. Abnormal albuminuria is relatively common and is closely associated with hypertension and glycaemic control. In the light of increasing prevalence of diabetes among overseas Chinese, our findings may have important implications in the management of Chinese diabetic patients.
PMCID: PMC2399753  PMID: 8497435
12.  17 alpha-Hydroxylase deficiency with persistence of müllerian ducts in a genotypic male and paradoxical aldosterone secretion. 
Postgraduate Medical Journal  1993;69(808):159-162.
We report a case of congenital adrenal hyperplasia due to 17 alpha-hydroxylase deficiency in a Chinese genotypic male patient. Despite the male genotype, normal female external genitalia were present and with the introduction of cyclical oestrogen therapy withdrawal bleeding occurred, confirming the presence of functional endometrial tissue. We believe this to be the first report of persistent Mullerian duct structures in a genotypic male with 17 alpha-hydroxylase deficiency. It could be explained by either impaired secretion or impaired action of anti-Mullerian hormone. Further, contrary to the usual finding of suppressed aldosterone secretion, this patient had measurable levels of plasma aldosterone.
PMCID: PMC2399616  PMID: 8506204
13.  Histiocytosis X involving the thyroid and hypothalamus. 
Postgraduate Medical Journal  1991;67(789):680-682.
A case of histiocytosis X involving the thyroid and hypothalamus is reported. A 16 year old female presented with amenorrhoea and diabetes insipidus. She subsequently developed a painful goitre with biochemical hypothyroidism, and stridor. The stridor and goitre responded to cyclophosphamide. Previous publications on the use of cytotoxics in histiocytosis X involving the thyroid are reviewed. We describe for the first time both the ultrasound appearances of the thyroid in this condition and the use of serial volumetric measurements to monitor therapy.
PMCID: PMC2399078  PMID: 1924059
14.  Virucidal properties of dimethyl sulfoxide. 
Applied Microbiology  1968;16(10):1625-1626.
PMCID: PMC547724  PMID: 4300900
15.  Quantitative measurement of intracellular RNA genomes of Rauscher murine leukemia virus by competition hybridization in DNA excess. 
Journal of Virology  1979;29(2):818-824.
The technique of competition hybridization in DNA excess was used to determine the intracellular distribution of RNA genomes of Rauscher murine leukemia virus. An examination of subcellular RNA fractions revealed that 59% of intracellular viral RNA genomes were associated with the nuclear-enriched fraction, 41% with the cytoplasmic fraction, and 18% with the polysomal-enriched fraction. Also, an analysis of total cellular RNA disclosed that 20% of intracellular viral RNA genomes were polyadenylated and 80% were not polyadenylated.
PMCID: PMC353222  PMID: 430612
16.  Quantitative nucleotide sequence relationships of mammalian RNA tumor viruses. 
Journal of Virology  1975;15(6):1396-1408.
A molecular hybridization technique has been used to quantitatively measure the nucleotide sequence relationships of selected mammalian RNA tumor viruses. Reciprocal cross-hybridization tests were done in which a given radioactively labeled, viral genomic RNA species was annealed with an excess of unlabeled, complementary DNA product synthesized in endogenously instructed reverse transcriptase reactions. Hybrid formation was measured with pancreatic RNase A. Three representative mammalian RNA tumor virus groups were examined: murine viruses, simian viruses, and feline viruses. The results of reciprocal cross-hybridization testing have revealed that the murine viruses consist of four distinctly related subgroups: (i) the Friend leukemia virus/Rauscher leukemia virus subgroup, (ii) the Gross leukemia virus subgroup, (iii) the Moloney sarcoma virus subgroup, and (iv) the Kirsten sarcoma virus subgroup. Simian sarcoma virus, the only simian virus examined, appeared to share limited interspecies sequence relationships with members of the other virus groups and in particular with Kirsten sarcoma virus. Of the two members of the feline virus group tested, Rickard feline sarcoma virus and RD-114, each was placed in a separate, unrelated subgroup. Rickard feline sarcoma virus exhibited limited sequence relatedness with members of the other virus groups, whereas RD-114 exhibited none.
PMCID: PMC354607  PMID: 49442
17.  The nucleotide sequence of a glutamate tRNA from rat liver. 
Nucleic Acids Research  1982;10(15):4605-4608.
A glutamate tRNA from rat liver was purified. By means of post-labeling techniques, its nucleotide sequence was shown to be: pU-C-C-C-A-C-A-U-m1G-G-U-C-psi-A-G-C- G-G-D-D-A-G-G-A-U-U-C-C-U-G-G-psi-U-mcm5s2U-U-C-A-C-C-C-A-G-G-C-G- G-C-m5C-m5C-G-G-G-Tm-psi-C-G-A-C-U-C-C-C-G-G-U-G-U-G-G-G-A-A-C-C-AOH. The sequence is remarkably similar to that of tRNA4Glu from Drosophila melanogaster. Only 10 out of 75 nucleotides in the two tRNAs are different.
PMCID: PMC321115  PMID: 6813824
18.  The nucleotide sequence of a glutamine tRNA from rat liver. 
Nucleic Acids Research  1982;10(12):3755-3758.
A glutamate tRNA from rat liver was purified. By means of post-labeling techniques, its nucleotide sequence was shown to be: pU-C-C-C-A-C-A-U-m1G-G-U-C-psi-A-G-C- G-G-D-D-A-G-G-A-U-U-C-C-U-G-G-psi-U-mcm5S2U-U-C-A-C-C-C-A-G-G-C-G- G-C-m5C-m5C-G-G-G-Tm-psi-C-G-A-C-U-C-C-C-G-G-U-G-U-G-G-G-A-A-C-C-AOH. The sequence is remarkably similar to that of tRNAGlu from Drosophila melanogaster. Only 10 out of 75 nucleotides in the two tRNAs are different.
PMCID: PMC320749  PMID: 6921629

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